15-88144779-T-C

Variant names:

• chr15-88144779-T-C
• rs3784405
• NM_001012338.3:c.464+2556A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001012338.3(NTRK3):​c.464+2556A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 152,070 control chromosomes in the GnomAD database, including 3,788 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (3788 hom., cov: 32)
• Consequence: NTRK3 NM_001012338.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.93
• Publications: 5 publications found

Genes affected

NTRK3 (HGNC:8033): (neurotrophic receptor tyrosine kinase 3) This gene encodes a member of the neurotrophic tyrosine receptor kinase (NTRK) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. Signalling through this kinase leads to cell differentiation and may play a role in the development of proprioceptive neurons that sense body position. Mutations in this gene have been associated with medulloblastomas, secretory breast carcinomas and other cancers. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2011]

NTRK3 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001012338.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK3	NM_001012338.3	MANE Select	c.464+2556A>G		intron	N/A	NP_001012338.1	X5D2R1
	NTRK3	NM_001375810.1		c.464+2556A>G		intron	N/A	NP_001362739.1	Q16288-1
	NTRK3	NM_001375811.1		c.464+2556A>G		intron	N/A	NP_001362740.1	X5D7M5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK3	ENST00000629765.3	TSL:1 MANE Select	c.464+2556A>G		intron	N/A	ENSP00000485864.1	Q16288-1
	NTRK3	ENST00000557856.5	TSL:1	c.464+2556A>G		intron	N/A	ENSP00000453959.1	Q16288-5
	NTRK3	ENST00000558676.5	TSL:1	c.464+2556A>G		intron	N/A	ENSP00000453511.1	H0YM90

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32882 AN: 151952 Hom.: 3784 Cov.: 32

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.192

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.216 AC: 32911 AN: 152070 Hom.: 3788 Cov.: 32 AF XY: 0.211 AC XY: 15722 AN XY: 74342

African (AFR) AF: 0.268 AC: 11105 AN: 41464

American (AMR) AF: 0.223 AC: 3406 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 624 AN: 3470

East Asian (EAS) AF: 0.161 AC: 829 AN: 5164

South Asian (SAS) AF: 0.184 AC: 888 AN: 4824

European-Finnish (FIN) AF: 0.134 AC: 1422 AN: 10592

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.206 AC: 14010 AN: 67964

Other (OTH) AF: 0.194 AC: 408 AN: 2108

Alfa AF: 0.189 Hom.: 1205

Bravo AF: 0.222

Asia WGS AF: 0.186 AC: 647 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.052
DANN	Benign	0.77
PhyloP100		-2.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3784405; hg19: chr15-88688010;